Nutritional compositions

ABSTRACT

Compositions for the promotion of muscle protein synthesis and control of tumor-induced weight loss in patients that are, for example, suffering from cancer cachexia, and methods of administering such compositions.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/412,370, filed Sep. 20, 2002; U.S. ProvisionalApplication No. 60/417,203, filed Oct. 9, 2002; and U.S. ProvisionalApplication No. 60/455,921 filed Mar. 19, 2003.

[0002] Disclosed are methods and nutritional compositions for thepromotion of muscle protein synthesis or the control of tumor-inducedweight loss, such as cancer cachexia.

[0003] Cachexia is a condition of severe malnutrition and negativenitrogen balance characterized by anorexia (i.e. a lack or severe lossof appetite), weight loss, and muscle atrophy. The physiological,metabolic, and behavioral changes in cachexia are associated withpatient complaints of weakness, fatigue, gastrointestinal distress,sleep/wake disturbances, pain, listlessness, shortness of breath,lethargy, depression, malaise and the fear of being burdensome on familyand friends. Although cachexia has been classically associated withchronic infections and malignant conditions, it has also been identifiedin patients after extensive traumatic injury and sepsis and in agingpersons with failure to thrive syndrome.

[0004] Loss of lean body mass associated with cancer cachexia not onlyweakens the individual and makes activities of daily living difficult,but can weaken the patient to the point that they do not have thestrength to undergo chemo-and/or radiation therapy.

[0005] Two main components contribute to cancer cachexia—a loss ofappetite and a metabolic response to stress that causes a preferentialloss of muscle at a rate greater than would be expected from the lack ofnutritional intake alone. Consequently, a nutritional supplement toameliorate the rate of loss of muscle mass in patients with cancer wouldhave an important clinical impact.

[0006] The inventors have found that when dietary intake is limitedbelow the optimal level for physiological or patho-physiologicalreasons, a dietary supplement must be more effective than normal foodintake in order to provide a benefit. This is because in thiscircumstance, when a dietary supplement is given, normal food intake islikely to be reduced by a calorically equivalent amount. Consequently, asupplement designed to limit cancer cachexia should stimulate muscleprotein synthesis to a greater extent than normal food intake and shouldnot interfere with the response to meal intake.

[0007] Trials of conventional nutritional supplements in patients withcancer cachexia have failed to show appreciable benefit in terms ofweight gain or quality of life. Accordingly, there is an urgent need foreffective nutritional approaches capable of treating, preventing orameliorating the effects of tumor-induced weight loss due to, forexample, cancer cachexia and/or anorexia.

[0008] The inventors have now found that a formulation containing freeessential amino acids, rather than intact protein, is optimal. Inparticular, and unexpectedly, the inventors have found that nutritionalcompositions comprising a mixture of essential amino acids in free formand/or in salt form, rather than intact protein, which mixture comprisesparticularly high amounts of leucine effectively stimulate muscleprotein synthesis.

[0009] The compositions of the present invention, e.g. in the form ofdietary means, e.g. supplements, or nutritional or pharmaceuticalformulations, for the treatment or prevention of cachexia, e.g. cancercachexia and/or anorexia can be self-administered for extensive periodswithout risk of adverse side-effects, yet have the potential to reversecachexia, e.g. cancer cachexia, and/or improve associated symptoms thataffect quality of life. The compositions as described herein haveexcellent taste and thus have particularly good patient compliance andpatient acceptance due to their increased ease of administration andingestion.

[0010] In one aspect of the present invention there is provided acomposition comprising at least one of isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine, or histidine,e.g. leucine and at least one of isoleucine, lysine, methionine,phenylalanine, threonine, tryptophan, valine, or histidine, in free formand/or in salt form, e.g. pharmaceutically or nutritionally acceptablesalt form, wherein leucine is present in an amount of at least about 10to about 95%, e.g. about 10 to about 60%, e.g. at least about 15, 20,25, 30 or 35% to about 40, 45, 50 or 55%, based on the weight ofamino-nitrogen source, hereinafter referred to as compositions of theinvention.

[0011] The term “amino-nitrogen source” as used herein refers to aminoacids, e.g. essential amino acids, conditionally essential amino acidsor non-essential amino acids, in free form or salt form, either alone orin combination with, e.g. in addition to, intact protein.

[0012] As used herein, the term “intact protein” refers to protein, e.g.hydrolyzed, e.g. partially hydrolyzed protein and to peptides, e.g. toamino acids which are not in free or salt form. According to theinvention, the “intact protein” may be chosen from at least one ofcasein, whey protein, soy protein, collagen or wheat protein.

[0013] In one aspect there is provided a composition of the invention,wherein leucine in free and/or salt form is present in amount of atleast about 10 to about 35%, e.g. about 11, 12, 13, 14 or 15 to about20, 25 or 30%, e.g. at least about 14 or 15% by weight, based on theweight of total amino acids.

[0014] In a further aspect of the invention there is provided acomposition of the invention wherein leucine is present in free formand/or salt form in an amount of at least about 20 to about 80%, e.g.about 20 to about 65%, e.g. about 25, 30 or 35% to about 40, 45, 50 or55%, e.g. about 65% by weight, based on the weight of amino acids infree form and/or salt form.

[0015] The term “amino acids” as used herein, unless otherwise stated,refers to amino acids in free form and/or in salt form chosen from atleast one of essential amino acids, e.g. isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine, or histidine,conditionally essential amino acids, e.g. tyrosine, cysteine, arginine,or glutamine, or non-essential amino acids, e.g. glycine, alanine,proline, serine, glutamic acid, aspartic acid, asparagines, taurine orcarnitine.

[0016] In yet a further aspect there is provided a composition of theinvention wherein leucine is present in free form and/or salt form in anamount of at least about 20 to about 95%, e.g. about 25, 30, 35, 40 or45% to about 50, 55, 60, 65, 70, 75, 80, 85 or 90%, e.g. about 95% byweight, based on the weight of essential amino acids in free form and/orsalt form.

[0017] The term “essential amino acids” (EAA) as used herein, unlessotherwise stated, refers to essential amino acids in free form and/orsalt form chosen from at least one of isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan, valine, and histidine.It is to be understood that “leucine” as used herein, unless otherwisestated, refers to leucine in free form and/or salt form.

[0018] The term “total leucine” or “total amino acid, e.g. essential orconditionally essential or non-essential amino acid” as used hereinrefers to leucine or amino acid in free and/or salt form plus leucine oramino acid derived from, or bound in, intact protein.

[0019] In a further aspect, there is provided a composition of theinvention, wherein total leucine, i.e. the sum of leucine in free and/orsalt form plus leucine derived from intact protein, is at least about 10to about 40%, e.g. at least about 15 to about 35%, e.g. at least about20 to about 30, e.g. about 21, 22, 23, 24 or 25%, e.g. about 22% byweight based on the weight of total amino acids. Total leucine contentof the compositions of the invention may be from about 25 to about 45,e.g. about 30 to about 40%, e.g. about 36% of the total essential aminoacids. The compositions of the invention may comprise leucine in freeand/or salt form:leucine in form of intact protein in a ratio of about3:1 to about 1:3, for example in a ratio of about 2: about 1. In oneaspect of the invention there is provided a composition of the inventioncomprising a ratio of total leucine:leucine in free and/or salt form ofabout 3:1 to about 1:3, e.g. about 1.5:1.

[0020] In yet a further aspect the present invention provides acomposition of the invention, wherein the amount of leucine, e.g. totalleucine, is up to three times higher than the highest amount of anyother essential amino acid, e.g. total essential amino acid.

[0021] The invention also relates to compositions further comprisingbranched-chain amino acids, e.g. valine, leucine, isoleucine, ormixtures thereof, in free and/or in salt form and/or in form of intactprotein, in an amount of about 30 to 60%, e.g. of about 35 to 55%, e.g.about 30 or 35 to 45% by weight based on the weight of amino-nitrogensource, e.g. of total amino acids.

[0022] In a further aspect of the invention there is provided acomposition of the invention with a reduced amount of tryptophan orhydroxytryptophan in free and/or in salt form and/or in form of intactprotein, e.g. about less than 5%, e.g. less than about 3% by weightbased on the weight of amino-nitrogen source, e.g. of total amino acids.

[0023] The invention also relates to compositions of the inventionfurther comprising threonine in free and/or in salt form and/or in formof intact protein in an amount of about 3 or 5 to about 11% by weightbased on the weight of amino-nitrogen source, e.g. of total amino acids.

[0024] In a further aspect the invention relates to compositions of theinvention further comprising valine in free and/or in salt form and/orin form of intact protein in amount of about 6% to about 16%, e.g. about8 to about 10% by weight based on the weight of amino-nitrogen source,e.g. based on the weight of total of amino acids.

[0025] In a further aspect of the invention the compositions of theinvention may further comprise conditionally essential amino acids infree and/or in salt form and/or in form of intact protein chosen from atleast one of arginine, glutamine, tyrosine, and cysteine.

[0026] In a preferred exemplary embodiment of the present invention, thecompositions of the invention comprise arginine in free form and/or saltform, e.g. in an amount of about 5% or 10% to about 40%, e.g. about 15%to about 25%, 30% or 35%, e.g. about 15 to 20% by weight based on theweight of amino-nitrogen source, e.g. of the total essential andconditionally essential amino acids. In one aspect, free arginineconstitutes about 5% to about 10%, e.g. about 7% of the total aminoacids of the compositions of the invention.

[0027] In yet another embodiment of the invention the compositions, e.g.pharmaceutical or nutritional compositions, of the invention may havethe following amino acid composition: leucine 20 to 35%, e.g. 30%,isoleucine 3 to 6%, e.g. 3 to 4%, valine 5 to 15%, e.g. 8 to 12%,methionine 0.5 to 7%, e.g. 2 to 5%, phenylalanine 8 to 12, e.g. 9 to10%, lysine 10 to 14%, e.g. 12 to 13%, threonine 8 to 12%, e.g. 9 to11%, histidine 8 to 12%, e.g. 8 to 11%, arginine 5 to 15% by weightbased on the weight of amino-nitrogen source, e.g. of total amino acids.In a further aspect the compositions of the invention may comprise thefollowing concentration rage of amino acids (% molar base): leucine 20to 40%, e.g. about 35 to 40%, isoleucine 3 to 10%, e.g. about 7%, valine5 to 15%, e.g. about 10%, methionine 0.5 to 7%, e.g. about 5%,phenylalanine 5 to 12, e.g. about 5%, lysine 8 to 20%, e.g. about 9%,threonine 6 to 12%, e.g. about 6%, histidine 3 to 8%, e.g. about 3%,tryptophan 0 to 4%, e.g. about 1%, arginine 5 to 15%, e.g. about 13%.The amino acids may be in free and/or in salt form and/or in form ofintact protein, e.g. in free form, or predominantly in free form. Inparticular, the compositions of the invention may comprise arginine,leucine and methionine in free form and/or salt form, for example in theamounts of about 5% to about 15% arginine, about 10% to about 30%leucine, and about 0.5% to about 5% methionine by weight based on theweight of amino-nitrogen source, e.g. of total amino acids. In a furtheraspect the compositions of the invention may comprisearginine:leucine:methionine in free form and/or salt form in a ratio ofabout 0.1 to about 5:about 0.5 to about 10:about 0.01 to about 1, e.g.in a ratio of about 0.5:about 1:about 0.05.

[0028] In a further aspect of the present invention the compositions ofthe invention may further comprise glutamine, e.g. glutamine peptide,e.g. in an amount of about 4 to 9 g per daily dose.

[0029] In yet a further aspect of the present invention, thecompositions of the invention further comprise intact protein, e.g.protein chosen from at least one of casein, whey protein, soy protein,collagen or wheat protein, preferably whey protein and/or soy proteinand/or casein may be used. For example, the invention provides acomposition comprising leucine in free form and/or in salt form andintact protein wherein leucine in free form and/or in salt form ispresent in an amount of about 10%, 15% or 20% to about 25%, 30% or 35%,e.g. about 15% to about 20%, e.g. about 18% by weight based on theweight of intact protein. The compositions of the invention may compriseintact protein:leucine in free and/or salt form in a ratio of about 10:1to about 1:10, for example in a ratio of about 5:1 to about 1:5, forexample in a ratio of about 5:1. The ratio of total amino acids:totalleucine may be from about 3:1 to about 6:1, e.g. about 4 to 5:1.

[0030] In one aspect, present inventors have found that particularlyhigh levels of essential and, optionally, conditionally essential aminoacids may be provided using compositions comprising a combination of

[0031] a) essential and, optionally, conditionally essential amino acidsin free and/or salt form, and

[0032] b) intact protein, wherein the ratio of total essential and,optionally, conditionally essential amino acids to total amino acids isfrom about 0.4 to about 0.95, e.g. about 0.45, 0.5, 0.55 or 0.6 to about0.7, 0.75, 0.8 or 0.9, e.g. about 0.65.

[0033] In one aspect the compositions according to the invention providea ratio of total essential and, optionally, conditionally essentialamino acids versus total non-essential amino acids of about 0.65:about0.45. In a further aspect the compositions of the invention compriseabout 40 to about 95%, e.g. about 45, 50, 55 or 60% to about 70, 75, 80or 90%, e.g. about 65% by weight of total essential and, optionally,conditionally essential amino acids based on the weight of total aminoacids.

[0034] In another exemplary embodiment of the present invention, thecompositions of the present invention comprise a mixture of essentialamino acids solely in free form and/or in salt form, e.g. leucine solelyin free form and/or in salt form and at least one essential amino acidsolely in free form and/or in salt form.

[0035] According to the present invention, the compositions of theinvention may be provided in form of dietary means, e.g. supplements, orin the form of a nutritional formulation, e.g. a medical food orbeverage product, e.g. in form of a complete meal, part of a meal, asfood additive or as powder for dissolution, or in the form of apharmaceutical formulation, e.g. in form of a tablet, pill, sachet orcapsule.

[0036] In a further aspect of the invention there is provided a medicalfood or beverage product, dietary supplement or nutritional orpharmaceutical formulation comprising a composition of the invention.

[0037] The compositions of the invention in form of dietary means, e.g.supplements, or pharmaceutical formulations may consist exclusively ofthe compositions of the invention, and optionally pharmaceutically ornutritionally acceptable carriers.

[0038] The compositions of the invention may be in medical food orbeverage product form, e.g. in form of a powder for dissolution. Thepowder may be combined with a liquid, e.g. water, or other liquid, suchas milk or fruit juice, e.g. in a ratio of powder to liquid of about 1to about 5, to obtain a ready-to-consume composition, e.g.ready-to-drink composition or instant drink.

[0039] Optionally, the compositions according to the invention may benutritionally complete, i.e. may include vitamins, minerals, traceelements as well as nitrogen, carbohydrate and fat and/or fatty acidsources so that they may be used as the sole source of nutritionsupplying essentially all the required daily amounts of vitamins,minerals, carbohydrates, fat and/or fatty acids, proteins and the like.Accordingly, the compositions of the invention may be provided in theform of a nutritionally balanced complete meal, e.g. suited for oral ortube feeding, e.g. by means of nasogastric, nasoduodenal, esophagostomy,gastrostomy, or jejunostomy tubes, or peripheral or total parenteralnutrition. Preferably the compositions of the invention are for oraladministration.

[0040] Surprisingly and unexpectedly, the present inventors have foundthat particularly useful compositions for promotion of muscle proteinsynthesis or controlling tumor-induced weight loss, such as cachexia,e.g. cancer cachexia, may be obtained by combining the mixture ofessential amino acids in free form and/or in salt form, alone or incombination with intact protein, as hereinabove described with n-3polyunsaturated fatty acids, including, but not limited to α-linolenicacid (LNA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA),either alone or in combination with each other. The effect of such acombination is greater than the effect that can be achieved with eithertype of combination partner alone, i.e. greater than the effect of anutritional therapy using only the mixture of essential amino acids infree form and/or in salt, alone or in combination with intact protein,or the n-3 fatty acid(s) as defined herein.

[0041] Hence, in one aspect the present invention further pertains to acombination comprising

[0042] (a) a mixture of essential amino acids in free and/or in saltform, wherein leucine, e.g. total leucine, is at least about 10 to about40%, e.g. at least about 15 to about 35%, e.g. at least about 20 toabout 30, e.g. about 15% to about 25%, e.g. about 22%, by weight basedon the weight of amino-nitrogen source, e.g. of total amino acids, and

[0043] (b) at least one n-3 fatty acid chosen from alpha-linolenic acid,eicosapentaenoic acid, and docosahexaenoic acid,

[0044] wherein leucine may be present in form of a combination ofleucine in free and/or salt form and leucine derived from intact proteinand the n-3 fatty acid(s) may be present in free form or in form of anoil or fat, e.g. for promotion of muscle protein synthesis orcontrolling tumor-induced weight loss, such as cachexia, e.g. cancercachexia.

[0045] Such a combination is preferably a combined preparation or apharmaceutical or nutritional composition.

[0046] Preferably the compositions of the invention may comprise EPA andDHA, e.g. EPA and DHA in a ratio of EPA:DHA of about 2:1 to about 1:2,e.g. about 1.5:1.

[0047] In a further aspect of the invention the compositions of theinvention may comprise EPA and DHA either alone or in combination, e.g.EPA alone, in an amount of at least about 600 mg to about 2 g, e.g.about 1.5 g to about 1.8 g per serving. When combined, EPA may bepresent in amount of about 500 mg to about 1.5 g, e.g. about 1 g, andDHA may be present in an amount of about 250 mg to about 1.5 g, e.g.about 500 mg to about 750 mg, e.g. about 650 mg, per serving.

[0048] In yet a further aspect of the invention the compositions of theinvention may comprise a mixture of n-6, e.g. linoleic acid, and n-3polyunsaturated fatty acids, e.g. chosen from linolenic acid, EPA andDHA, e.g. in a ratio of n-6:n-3 polyunsaturated fatty acids of about0.1:1 to about 1:0.1, e.g. about 0.2, 0.5 or 0.8 to about 1, 1.2 or 1.5,e.g. about 1.1:1.

[0049] In a further aspect the compositions of the invention maycomprise about 2 g or 2.5 to about 3.5 g, e.g. about 2.5 g or 3 g perserving of monounsaturated fatty acids (MUFA) and about 3 g or 3.5 g toabout 4 g or 6 g, e.g. about 4.5 g or 5 g per serving of polyunsaturatedfatty acids (PUFA).

[0050] Nutritional formulations comprising the compositions of theinvention, e.g. medical food or beverage product, comprise othernutritional components, e.g. fats and/or carbohydrates, in addition tothe mixture of essential amino acids in free and/or in salt form andoptionally the n-3 fatty acid(s). Dietary oils may be used in thepreparation of the nutritional compositions of the invention. Dietaryoils include but are not limited to canola, medium chain triglycerides(MCT), fish, soybean, soy lecithin, corn, safflower, sunflower,high-oleic sunflower, high-oleic safflower, olive, borage, blackcurrant, evening primrose and flaxseed oil. Preferably fish oil may beused, e.g. an oil comprising about 45% EPA and about 10% DHA, e.g. asknown and commercially available under the trade name EPAX® 4510 fromPronova Biocare (Lysaker, Norway), or concentrated fish oil, comprisinge.g. about 70% EPA.

[0051] The dose of dietary oil per serving, e.g. in the form of fishoil, may comprise for example about 0.5 g to about 3 g, e.g. about 1.5 gto about 2 g, of n-3 polyunsaturated fatty acids.

[0052] The dose of dietary oil per serving may comprise for exampleabout 2.5 g, 3.5 g or 4.5 g to about 5.5 g, 6.5 g or 7.5 g, e.g. about5.5 g of fish oil and/or about 0.5 g, 1 g, 1.5 g, 2 g or 2.5 g to about3 g, 3.5 g, 4 g, 4.5 g or 5 g, e.g. about 1 g to about 3 g, e.g. about 1g of medium chain triglycerides (MCT).

[0053] According to the invention, up to 5 or 6, e.g. about 2 to 3servings may be given per day.

[0054] In a further aspect of the present invention the compositions ofthe invention, e.g. nutritional compositions, may further comprisesoluble fibers, e.g. agar, alginates, carubin, pectin and itsderivatives, e.g. pectins from fruits and vegetables, and morepreferably pectins from citrus fruits and apple, beta-glucan, such asoat beta-glucan, carrageenans, e.g. kappa, lambda and iota carrageenans,furcellaran, inulin, arabinogalactan, cellulose and its derivatives,scleroglucan, psyllium, such as psyllium seed husk, mucilages and gums.According to the invention, gums and mucilages are preferably plantexudates. In particular, the term “gum” as used herein refers to thecommonly available vegetable gums and more particularly to konjac gum,xanthan gum, guar gum (guaran gum), locust bean gum, tara bean gum, gumtragacanth, arabic gum, karaya gum, gum ghatti, gellan gum and otherrelated sterculia gum, alfalfa, clover, fenugreek, tamarind flour.Native and modified, e.g. hydrolyzed, soluble fibers may be usedaccording to the invention. According to the invention, preferably guargum, e.g. hydrolyzed guar gum, may be used.

[0055] The compositions of the invention may further deliver about 5 gto about 15 g per day, e.g. about 9 g per day soluble fiber, for examplein the form of inulin and hydrolyzed guar gum, e.g. in 3 servings ofabout 3 g.

[0056] In one embodiment of the present invention the daily delivery ofamino-nitrogen source may be from about at least 10 g to about 60 g,e.g. from about 15 g to about 55 g, e.g. about 20 to about 50 g, e.g.about 44 to about 54 g. Optimally at least about 6 g to about 18 g, e.g.about 10 g to about 12 g of the total amino-nitrogen source per dailydose are amino acids in free form and/or in salt form. At least about 3g up to about 15 g, e.g. about 6 g, 7.5 g, 8 g or 8.5 g to about 12 g,e.g. about 8 g of the total amino-nitrogen source per daily dose areessential amino acids in free form and/or in salt form. The daily doseof e.g. about 15 g essential amino acids, e.g. in free and/or salt form,may be given 3 times per day, e.g. in 3 servings of about 5 g, withequal effectiveness. In one aspect the daily delivery of leucine in freeand/or salt form may be from about 5 g to about 10 g, e.g. in an amountof about 8 g. The daily delivery of total leucine may be from about 10 gto about 20 g, e.g. about 12 g to about 15 g, e.g. about 12 g. In oneaspect of the invention total essential and, optionally, conditionallyessential amino acids may be delivered in an amount of from about 6 toabout 21 g per serving, e.g. from about 6 to about 12 g per serving.

[0057] The daily delivery of the optional nutrients referred tohereinabove may vary depending on body weight, sex, age and/or medicalcondition of the individual. All indicated proportions described aboveare accordingly to be understood as being indicative of preferred orindividually inventive teaching only and not limiting the invention inits broadest aspect.

[0058] In a further embodiment of the invention, the nutritional productprovides at least 100%, e.g. 100%, of the U.S. RDA for vitamins andminerals per daily dose.

[0059] The present inventors have found that particularly high amountsof vitamin E are useful in the compositions as hereinabove described forpromotion of muscle protein synthesis or controlling tumor-inducedweight loss, such as cachexia, e.g. cancer cachexia.

[0060] Hence, in a further aspect the invention also pertains tocompositions of the invention further comprising tocopherol and/ortocotrienol, e.g. Vitamin E (α-tocopherol), in an amount of about 50 mgto about 400 mg, e.g. about 100 mg or 200 mg to about 300, e.g. about150, 240 mg or 300 mg per daily dose, e.g. in three servings of about 50or 100 mg.

[0061] The caloric density of the compositions, e.g. nutritionalcompositions of the invention may be about 1.5 kcal/mL, e.g. about 600to about 1500 kcal per day, e.g. about 720 to about 900 kcal per day, inthe form of about two to about five or six servings per day, e.g. inthree servings of about 310 kcal. A suitable serving size may be in therange of about 20 to about 500 ml, preferably about 50 to about 250 ml,e.g. about 200 or 240 ml. The compositions of the invention may providebenefit with as few as for example two servings per day. Levels ofamino-nitrogen source, e.g. intact protein or amino acids, e.g.essential amino acids, or fatty acids, or carbohydrate on a per literbasis are not crucial, provided that a reasonable volume supplies therecommended amounts in accordance with the invention. A typicalnutritional composition useful according to the invention will have acaloric distribution of about 12 to about 24%, e.g. about 23% from asource of amino nitrogen, e.g. protein, e.g. amino acids in free formand/or in salt form in combination with intact protein, about 40 toabout 65%, e.g. about 46% from carbohydrate, for example in the form ofmaltodextrin and sucrose, and about 10 to about 35%, e.g. about 30% fromfat, for example in the form of fish and vegetable oil.

[0062] Nutritional compositions in accordance with the present inventionmay be provided as a medical food or beverage product, e.g. in oralnutritional form, e.g. as a health drink, as a ready-made drink,optionally as a soft drink, including juices, milk-shake, yogurt drink,smoothie or soy-based drink, in a bar, or dispersed in foods of anysort, such as baked products, cereal bars, dairy bars, snack-foods,soups, breakfast cereals, muesli, candies, tabs, cookies, biscuits,crackers (such as a rice crackers), and dairy products.

[0063] Preferably the compositions of the invention may be administeredas a nutritional formulation, e.g. as part of a meal, e.g. in the formof a health drink, e.g. ready-to-use drink.

[0064] Nutritional compositions in accordance with the present inventionmay be administered in form of a single composition that contains allcomponents, e.g. essential amino acids, fatty acids and/or solublefibers, or each component may be administered individually. For examplea liquid nutritional formulation, e.g. in the form of a syrup,suspension, emulsion or solution, may contain all components except forthe essential amino acids, e.g. except for the branched-chain aminoacids and/or glutamine, e.g. glutamine peptide, if present. For example,the branched-chain amino acids and/or glutamine, e.g. glutamine peptide,if present, may be administered in form of a solid oral dosage form,e.g. in form of a capsule, pill, tablet, dragées, or sachet.

[0065] Solid oral dosage forms are prepared in a manner known per se,for example by means of conventional mixing, granulating, confectioning,dissolving or lyophilizing processes.

[0066] For example, compositions for oral administration may be obtainedby combining the active ingredients with solid carriers, optionallygranulating a resulting mixture and processing the mixture or granules,if desired or necessary after the addition of suitable excipients, toform tablets or dragée cores.

[0067] Suitable physiologically acceptable carriers may be especiallyfillers, such as sugars, for example lactose, mannitol or sorbitol,cellulose preparations and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, and also binders, such asstarch pastes using, for example, corn, wheat, rice or potato starch,gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and,if desired, disintegrators, such as the above-mentioned starches, andalso carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, oralginic acid or a salt thereof, such as sodium alginate. In one aspectof the invention the compositions of the invention may be lactose-free.Further excipients may be especially flow-conditioners and lubricants,for example silicic acid, talc, stearic acid or salts thereof, such asmagnesium or calcium stearate, and/or polyethylene glycol. Dragée coresare provided with suitable coatings, there being used inter aliaconcentrated sugar solutions which may contain Arabic gum, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orcoating solutions in suitable organic solvents or solvent mixtures. Dyesor pigments may be added to the tablets or dragée coatings, for examplefor identification purposes or to indicate different doses of activeingredient.

[0068] Other orally administrable compositions may be in the form ofhard gelatin capsules or soft, sealed capsules consisting of gelatin anda plasticizer, such as glycerol or sorbitol. The hard gelatin capsulesmay comprise the composition of the invention in the form of granules,for example in admixture with fillers, such as lactose, binders, such asstarches, and/or glidants, such as talc or magnesium stearate, and, ifdesired, stabilizers. In soft capsules the composition of the inventionis preferably dissolved or suspended in suitable liquids, such as fattyoils, paraffin oil or liquid polyethylene glycols, it is likewise beingpossible to add stabilizers.

[0069] Conventional additives may be included in the compositions of theinvention, including any of those selected from preservatives, chelatingagents, osmotic agents, buffers or agents for pH adjustment,effervescing agents, sweeteners, e.g. artificial sweeteners, flavoringagents, coloring agents, taste masking agents, acidulants, emulsifiers,stabilizers, thickening agents, suspending agents, dispersing or wettingagents, antioxidants, acidulants, texturizers, antifoams, and the like.

[0070] In addition to the foregoing the present invention also providesa process for the production of a composition, e.g. nutritional orpharmaceutical formulation, as hereinbefore defined, which processcomprises bringing the individual components thereof into intimateadmixture and, when required compounding the obtained composition in afood or beverage product, for example ready-made drink, or in unitdosage form, for example filling said composition into gelatin capsules.

[0071] In another aspect the present invention provides a method forcontrolling tumor-induced weight loss, such as cachexia, e.g. cancercachexia, e.g. treating or preventing or ameliorating the effects ofcachexia, e.g. cancer cachexia, and/or anorexia, comprising enterallyadministering to a human in need of such treatment any compositiondisclosed herein.

[0072] In yet a further aspect the present invention provides forpromotion of or stimulating muscle protein synthesis, or amelioratingloss of muscle in a human comprising enterally administering to a humanin need of such treatment a composition of the invention.

[0073] In yet a further aspect the invention provides a method ofpreventing catabolism and increasing protein synthesis in a subjectundergoing metabolic stress, which comprises administering to a human inneed of such treatment a composition of the invention.

[0074] The invention further provides a use of the compositions asdescribed herein for the dietary management of malnutrition, e.g.protein-energy malnutrition.

[0075] In yet another aspect of the invention there is provided a use ofthe compositions of the invention in the manufacture of a medicament forthe treatment and/or prevention of tumor-induced weight loss, such ascachexia, e.g. cancer cachexia, and/or anorexia, ameliorating theeffects of cachexia, e.g. cancer cachexia, and/or anorexia, stimulatingmuscle protein synthesis, or ameliorating loss of muscle in a human.

[0076] The method of treatment or use as claimed herein is applicable totumor-induced weight loss, such as cancer cachexia, or anorexia in humanpatients suffering from different cancers, e.g. liver, breast, lung,prostate, gastrointestinal or pancreatic cancer. Cachexia or anorexiamay be related to the disease itself or the effects of treatment.

[0077] The method of treatment or use according to the invention may becombined with pharmacological and alternative/complementary medicinetherapies and/or with educational interventions, e.g. to treat andmanage the physical and emotional symptoms associated with cachexia,e.g. cancer cachexia, and/or anorexia. For example, the compositions ofthe invention may be combined with anti-cancer drugs, such as5-fluorouracil, mitomycin-C, adriamycin, chloroethyl nitrosureas andmethotrexate. In a further aspect the compositions may be combined withinterleukin-15.

[0078] In a further aspect of the present invention there may beprovided a combined pharmaceutical formulation for simultaneous,separate or sequential use for the treatment or prevention of cachexia,e.g. cancer cachexia, and/or anorexia comprising a composition of theinvention, and one or more anti-cancer drug(s).

[0079] Dependent on the form of application of the compositions of theinvention, i.e. as complete meal, part of a meal, food additive, drink,sachet, tablet or capsule, the compositions of the invention may betaken once daily to five or six times daily. For patients using thecompositions of the invention as a supplement to a normal diet, thedaily dose may be two servings per day. For patients receiving thecompositions of the invention as their entire daily nutritional intake,up to six servings per day may be recommended. The compositions of theinvention may be served without restriction to time of day, e.g.together with the main meals, preferably between meals.

[0080] The compositions of the invention may be administered under thesupervision of a medical specialist, or may be self-administered.

[0081] For treatment of tumor-induced weight loss, such as cachexia,e.g. cancer cachexia, and/or anorexia under clinical supervision it ispossible to combine the nutritional approach with conventionalpharmaceutical therapies such as anti-cancer drugs. The anti-cancerdrugs may conveniently be formulated together with the compositions ofthe invention in standard pharmaceutical dosage forms. In a furtheraspect of the invention the composition of the invention may be providedin form of a kit for separate, sequential or simultaneous administrationin conjunction with one or more anti-cancer drug(s).

[0082] Optimally, the composition, e.g. nutritional composition ordietary supplement, of the invention is consumed for the duration ofpatient care and treatment, e.g. until weight is regained or lean bodymass is increased. Since these formulations are safe to consume,cachectic or anorectic patients, can continue taking these supplementsfor as long as required, e.g. until normal weight or lean body mass hasbeen resumed. Early intervention may be a critical success factor forimproved outcome in patients with cachexia, e.g. cancer cachexia.

[0083] Anyone perceived to be at risk from tumor-induced weight loss,e.g. cachexia and/or anorexia or subjects already suffering fromcachexia, e.g. cancer cachexia, and/or anorexia, can benefit fromingesting the compositions of the invention. The compositions of theinvention may be particularly indicated for patients with solid tumorswith cachexia or at risk of developing it. By stimulating muscle proteinanabolism, the compositions of the invention have the potential toreduce the rate of or reverse tumor-induced weight loss, e.g. cachexia,to promote weight gain, stimulate muscle growth, enhance immunefunction, restore metabolic balance, support increased resistance toinfection, improve tolerance to cancer therapy, enhance response tocancer therapy, reduce morbidity, improve associated symptoms thataffect quality of life, such as weakness, fatigue, gastrointestinaldistress, sleep/wake disturbances, pain, listlessness, shortness ofbreath, lethargy, depression, malaise.

[0084] In accordance with the invention as presently claimed it ispossible to effectively ameliorate symptoms and conditions associatedwith tumor-induced weight loss, e.g. cachexia and/or anorexia withnatural compounds, which do not show any severe side effects. Further,the present methods are well-tolerated, for example without causing anydiscomfort or nausea, and simple to apply.

[0085] The utility of all the compositions of the present invention maybe observed in standard clinical tests in, for example, indications asdescribed hereinabove, for example using dosages of amino acids in freeform and/or in salt form, in the range of about 0.05 to about 0.3 g/kgbody weight/day, preferably from about 0.085 to about 0.25 g/kg bodyweight/day, more preferably from about 0.1 or 0.15 to about 0.2 g/kgbody weight/day, or using dosages of total essential amino acids in therange of from about 6 to about 12 g or up to about 21 g per serving, orfrom about 36 to about 72 g total essential amino acids per day, for amammal, e.g. adult, and in standard animal models. The effect of thecompositions of the invention, on prevention and treatment oftumor-induced weight loss, e.g. cachexia can be monitored by any of themethods known to one skilled in the art, e.g. food intake, body weight,anthropometric measurements, serum levels of lipids, fatty acids, aminoacids, levels of serologic markers, serotonin, C-reactive protein, TNFalpha, IL-1, changes in the morphology of tumors.

[0086] One human clinical trial may be affected as follows:

[0087] A randomized double blind study comparing the compositions of theinvention, e.g. using dosages of amino acids in free form and/or in saltform, in the range of about 0.05 to about 0.3 g/kg body weight/day,preferably from about 0.085 to about 0.25 g/kg body weight/day, morepreferably from about 0.1 or 0.15 to about 0.2 g/kg body weight/day anddosages of n-3 polyunsaturated fatty acids in the range of about 0.05 toabout 0.3 g/kg body weight/day, preferably from about 0.06 to about 0.2g/kg body weight/day, more preferably from about 0.06 to about 0.13 or0.15 g/kg body weight/day, or using dosages of total essential aminoacids in the range of from about 6 to about 12 g or up to about 21 g perserving, or from about 36 to about 72 g total essential amino acids perday, to a standard nutritional supplement may be performed in patientswith advanced pancreatic cancer aiming at comparison of the effect onlean body mass, assessment of the effect on mediators in serum andurine, pro-inflammatory cytokines and muscle metabolism, and assessmentof changes in performance status, quality of life and survival. 125patients per treatment group may be tested, e.g. assessing the followingparameters:change in lean body mass between baseline and week 12, bodyweight, nutritional intake and fatty acid analysis. In addition, for asubgroup of forty patients, baseline versus three weeks investigationsmay be undertaken for: Urinary Proteolysis Inducing Factor, acute phaseprotein response (C-reactive protein concentration) and pro-inflammatorycytokines, Ubiquitin metabolism (muscle biopsy in 15 patients) and theacceptability of the product, e.g. taste, and compliance with thetreatment regimen.

[0088] The invention will now be further illustrated by the followingexamples.

EXAMPLE 1

[0089] An experiment was performed in healthy older subjects ({overscore(x)}=71±2 yr) to determine if non-essential amino acids, i.e. aminoacids synthesized within the body at a rate sufficient to provide dailyrequirements, are needed for an amino acid mixture to stimulate muscleprotein synthesis. The response of muscle protein metabolism to either18 g of essential amino acids (EAAs) or 40 g of balanced amino acids(BAA, EAAs+22 g non-essential amino acids) given orally over athree-hour period was compared. Muscle protein metabolism was measuredin the basal state and during oral amino acids using L-²H₅-phenylalanineinfusion, femoral arterial and venous catheterization, and musclebiopsies. The exact mixtures of amino acids tested are shown in Table 1.TABLE 1 Amino acids content of the two supplements administered to thetwo groups of older subjects. The supplements were made of crystallineamino acids and dissolved in 540 ml of water containing a sugar-freeflavor. Essential Balanced Amino Acids Amino Acids Alanine (g) — 2.4Arginine (g) — 2.8 Asparagine (g) — 3.7 Cysteine (g) — 0.5 Glutamine (g)— 5.8 Glycine (g) — 1.8 Histidine (g) 2.0 2.0 Isoleucine (g) 1.9 1.9Leucine (g) 3.2 3.2 Lysine (g) 3.9 3.9 Methionine (g) 1.0 1.0Phenylalanine (g) 1.6 1.6 Proline (g) — 1.9 Serine (g) — 1.6 Threonine(g) 1.9 1.9 Tryptophan (g) 0.5 0.5 Tyrosine (g) — 1.4 Valine (g) 2.2 2.2Total Amino Acids (g) 18.2 40.1 Total Energy (kJ [kcal]) 309 [74] 682[163]

[0090] Results Net muscle protein synthesis (reflected by phenylalaninekinetics) increased similarly from basal (p<0.01) in both groups (BAA:−16±5 to 16±4); EM: −18±5 to 14±13 nmol·⁻¹·100 ml leg⁻¹) due to asimilar increase (p<0.01) in muscle protein synthesis (BAA: 43± to67±11; EAA: 62±6 to 75±10 nmol·min⁻¹·100 ml leg⁻¹) and no change inbreakdown. The results indicate that essential amino acids are solelyresponsible for the amino acid-induced stimulation of muscle proteinanabolism.

EXAMPLE 2

[0091] The effect of a mixture of free essential amino acids on muscleprotein synthesis stimulation was compared with the effect of a sameamount of protein. Elderly volunteers (n=5) were given 15 g of freeessential amino acids (leucine, isoleucine, methionine, phenylalanine,histidine, lysine, and threonine) on one occasion and 15 9 of wheyprotein on another. The results are shown in FIGS. 1 and 2. Net muscleprotein synthesis, i.e. the balance between protein synthesis andbreakdown, was measured using the A-V balance technique and stableisotope tracers, as described in Biolo et al, Am J Physiol.267(39):E467-474, 1994, which is hereby incorporated by reference. Eventhough whey protein is a rapidly absorbed protein, as compared to otherproteins such as casein, the change in plasma phenylalanineconcentration (representative of all EAAs) was modest and transient(see, FIG. 1). In contrast, phenylalanine concentration peaked rapidlyand at a much higher concentration after ingestion of the free EAAs(see, FIG. 2). The response of net protein synthesis is also shown inFIGS. 1 and 2. The pattern of net balance corresponded to the changes inconcentration. The total response to the EAA drink was more than twicethat of the intact protein, even though comparable amounts of N wereingested (see, FIG. 3). The results indicate that ingestion of EAAs ismore effective than ingestion of a comparable amount of intact proteinin stimulating net muscle protein synthesis in unstressed elderlyindividuals.

[0092]FIG. 1 shows response of plasma phenylalanine concentration andnet balance (reflection of net protein synthesis) to ingestion of 15 gof whey protein.

[0093]FIG. 2 shows phenylalanine concentration and net balance inresponse to 15 g of a solution of essential amino acids (EAAs).

[0094]FIG. 3 shows comparison of total response of net muscle proteinsynthesis to EAAs vs whey protein. Significantly different, p<0.001.

EXAMPLE 3

[0095] To investigate the optimal mixture of free amino acids forstimulating net muscle protein synthesis a series of studies in NewZealand white rabbits weighing about 4.5 kg was performed. Net muscleprotein balance was quantified by a technique analogous to the one usedfor human studies as described in Biolo et al, J Parent Enteral Nutr16:305-315, 1992, which is hereby incorporated by reference, except thatleg blood flow was measured by flow probe. This animal model is designedto represent a stress model induced by the surgical procedures needed tocollect the samples and therefore is considered to be a good model for aseriously-ill cancer patient. Different amino acid mixtures were infusedinto the rabbits, and the response of muscle quantified.

[0096] The groups were as follows: Controls: No amino acids AA group: Abalanced AA solution (10% TRAVASOL ®) containing all amino acids (27.3umol · kg⁻¹ · min⁻¹) EAA group: Only essential amino acids (27.3 umol ·kg⁻¹ · min⁻¹) Leu (25%) + Leucine was added to the balanced AA solutionto AA group: account for 25% of total nitrogen and infused at the sametotal nitrogen group as others (27.3 umol · kg⁻¹ · min⁻¹) Leu (35%) +Same as above, except Leu comprised 35% of total AA group: Leu only:Leucine only at 8.3 umol · kg · min

[0097] The amino acid composition of each mixture is shown in Table 2.TABLE 2 Amino acid composition in 100 ml of the infusion solutions. LeuBalanced EAA (25%) + AA Leu (35%) + AA Leu Leu  730 mg 1.86 g 3.63 g5.02 g 4.37 g Ile  600 mg 1.01 g  472 mg  390 mg 0 LysHCI  580 mg 1.56 g 456 mg  377 mg 0 Val  580 mg 1.15 g  456 mg  377 mg 0 Phe  560 mg 1.56g  441 mg  287 mg 0 His  480 mg 1.09 g  378 mg  312 mg 0 Thr  420 mg1.47 g  330 mg  273 mg 0 Met  400 mg 0.31 g  315 mg  260 mg 0 Trp  180mg 0.11 g  142 mg  117 mg 0 Ala 2.07 g 1.63 g 1.35 g 0 Arg 1.15 g  905mg  748 mg 0 Gly 1.03 g  810 mg  670 mg 0 Pro  680 mg  535 mg  442 mg 0Ser  500 mg  393 mg  325 mg 0 Tyr   40 mg   31 mg   26 mg 0

[0098] Table 3 compares the amount of leucine infused as a function oftotal N. TABLE 3 (1) Leucine infusion Leu infused Total N infused % ofLeu Solution μmol · kg⁻¹ · min⁻¹ μmol · kg⁻¹ · min⁻¹ to total NTRAVASOLI ® 1.39 27.3  5% EAA 4.37 27.3  16% Leu (25%) + AA 6.93 27.3 25% Leu (35%) + AA 9.58 27.3  35% Leu alone 8.75 8.75 100%

[0099] The results are shown in Table 4. TABLE 4 Protein kinetics inmuscle Synthesis Breakdown Net balance Control (n = 6) 5.4 ± 0.6 9.2 ±1.1 −3.8 ± 0.5 TRAVASOL ® (n = 6) 4.3 ± 0.7 8.7 ± 1.0 −4.4 ± 1.0 EAA (n= 4) 4.6 ± 1.2 9.5 ± 1.7 −4.9 ± 0.6 Leu (25%) + AA (n = 6) 6.8 ± 1.1*8.1 ± 1.2 −1.2 ± 0.2* Leu (35%) + AA (n = 8) 6.9 ± 0.6* 8.0 ± 0.4 −1.0 ±0.4* Leu alone (n = 5) 6.6 ± 0.7 9.2 ± 0.5 −2.6 ± 0.3

[0100] Neither a balanced solution, nor the EAA solution, stimulated netmuscle synthesis at the dosage given. In contrast, when the mixture wasenriched with leucine a stimulatory effect on synthesis was observed.

EXAMPLE 4

[0101] Mixtures of EAAs+arginine for nutritional supplement effective inameliorating loss of muscle in cancer patients. Values are % of totalamino acids (molar base). 4.4 4.1 4.2 4.3 Range Leucine 30 30 38.8 25-40Isoleucine 3 4 7.4  3-10 Valine 9 8 10.4  5-10 Methionine 3 5 4.6 1-5Phenylalanine 10 9 5.5  5-12 Lysine 13 12 9.4  8-20 Threonine 9 11 6.4 6-12 Histidine 8 11 3.4 3-8 Arginine 15 10 13.0 10-15 Tryptophan — —1.2 1-4 100 100 100  62-115

EXAMPLE 5

[0102] A cancer supplement in form of a ready to drink composition.

EXAMPLE 5A

[0103] Percent Grams/serv. Water 66.6667 176.667 Canola oil 1.8567 4.920MCT oil 1.0411 2.759 EPAX ® 4510 (Marine Oil) 1.1878 3.148 DHA Gold ®(Algae Oil) 0.3511 0.930 Ca caseinate 6.8900 18.259 Partially hydrolyzedguar gum 1.6978 4.499 Arginine 0.6944 1.840 Leucine 0.5511 1.460 Valine0.2978 0.789 Methionine 0.0300 0.080 Phenylalanine 0.2456 0.651 Sucrose7.6089 20.164 Corn Syrup (25DE) 9.4344 25.001 Potassium citrate 0.18890.501 Sodium citrate 0.1889 0.501 Lactic Acid 0.0444 0.118 Flavor 0.39891.057 Sucralose 0.0700 0.186 Sodium chloride 0.0400 0.106 Mono- andDiglycerides 0.1322 0.350 Antifoam 0.0022 0.006 Sodium ascorbate 0.03000.080 Vit/Min Premix 0.3511 0.930 Total (per 100 g) 100.000 265.000Total (per serving) 265 Grams

EXAMPLE 5B

[0104] Grams per Formula Serving Percent Water 173.95 65.6410 MCT oil1.2 0.4528 Canola oil 0.6 0.2264 Sun oil 4.5 1.6981 EPAX ® 3000TG 5.72.1509 Mixed tocopherols 0.0024 0.0009 Ca caseinate 18.26 6.8905Partially hydrolyzed guar gum 1.35 0.5094 Fructooligosaccharide 2.30.8679 Arginine 1.49 0.5623 Leucine 3.13 1.1811 Methionine 0.18 0.0679Sucrose 9 3.3962 25DE corn syrup 38 14.3395 Potassium citrate 0.5 0.1887Sodium citrate 0.5 0.1887 Lactic acid 1.25 0.4717 Flavor 0.8 0.3019Flavor 0.4 0.1509 Sucralose 0.132 0.0498 Salt 0.2 0.0755 Monos andDiglycerides 0.490 0.1849 Lecithin 0.133 0.0502 Antifoam 0.0045 0.0017Sodium ascorbate 0.08 0.0302 Vit/Min Premix 0.85 0.3208 265.0019 100.000

[0105] Method: Water is heated to 160° F. and all ingredients except forEPAX® 4510, DHA GOLD®, flavor, sucralose, sodium chloride, sodiumascorbate and lactic acid are added. The mixture is cooled to less than100° F. and the pH adjusted to 6.5 with lactic acid. The mixture isheated to 140° F. under agitation and after five minutes holding timehomogenized at 2500 psi. The remaining ingredients are added and themixture preheated to 150° F., heated at 290° F. for sec and homogenizedat 2500 psi.

[0106] For example, the vitamin/mineral pre-mix may comprise thefollowing: Maltodextrin powder DE 37.404155 Dipotassium phosphate35.701500 Magnesium oxide 8.330400 Vitamin E acetate 7.168900 Tricalciumphosphate 4.760200 Ferrous sulfate 1.387600 Zinc sulfate 1.042500Biotin, 1% trituration 0.933000 Niacinamide (B₃) 0.761600 Vitamin Apalmitate 0.606900 Calcium pantothenate 0.430800 Copper gluconate0.380800 Vitamin K 0.297500 Cyanocobalamin (B₁₂) 0.202300 Manganesesulfate (monohydrate) 0.172860 Vitamin D₃ 0.119000 Pyridoxinehydrochloride (B₆) 0.095200 Potassium iodide 10% 0.055258 Thiaminehydrochloride (B₁) 0.054700 Riboflavin (B₂) 0.054700 Chromic acetate(monohydrate) 0.015480 Folic acid 0.015333 Sodium molybdate (dihydrate)0.005160 Sodium selenite (anhydrous) 0.004154 Total 100.000000

[0107] The individual components can be sourced from the followingsources.

[0108] Canola oil is from Columbus Foods (Chicago, Ill.).

[0109] MCT oil is from Stepan Company (Northfield, Ill.).

[0110] EPAX® 4510 (Marine oil) is from Pronova Biocare (Lysaker, Norway)

[0111] DHA GOLD® (Algae oil) is from Martek Biosciences Corporation(Columbia, Md.)

[0112] Calcium caseinate is from New Zealand Milk Products (Weston,Fla.)

[0113] Hydrolyzed guar gum is from Novartis Nutrition Corporation(Minneapolis, Minn.)

[0114] Arginine, Leucine, Valine, Methionine, Phenylalanine, are fromAjinomoto (Raleigh, N.C.)

[0115] 25 DE corn syrup is from Cargill, Inc. (Minneapolis, Minn.)

[0116] Vit/min Premix is from Fortitech Inc. (Schenectady, N.Y.)

[0117] Mono- and diglycerides are from American Ingredients Inc.(Anaheim, Calif.)

[0118] Antifoam is from Dow Corning Corp. (Midland, Mich.)

EXAMPLE 6

[0119] A cancer supplement in form of a ready to drink composition. Thecomposition is prepared according to the method described in Example 5.G/100 ml Water 72.7655747 Protein Na-caseinate 5.2320000 Ca-Caseinate2.3980000 L-Leucine 1.3050003 L-Arginine 0.6199996 L-Methionine0.0752100 Fat Fish oil 2.8002100 Sunflower oil 2.0100003 MCT oil0.5003100 Carbohydrate Inulin 1.1172500 Sucrose 1.0900000 Maltodextrin16.5445530 Fructose 0.5450000 Partially hydrolyzed guar gum 0.5253800Vitamin E (α-tocopherol) 0.0763000 Vitamins/Minerals 0.2235515 Flavor0.7517000 Stabilizer 0.0893778 Sweetener 0.0654000 K2H-citrate 0.1962000K-citrate 0.0599500

[0120] Equivalent compositions may be obtained employing 0.0327 gVitamin E per 100 ml.

[0121] The examples illustrate compositions useful for example toprovide sources of amino acids to counteract protein-energymalnutrition, to optimize protein synthesis and muscle buildingcapacity, help restore and maintain muscle mass and weight, support apotentially improved response to cancer treatment and improve quality oflife, on administration of for example from one to six servings of 200ml per day.

[0122] It is understood that while the present invention has beendescribed in conjunction with the detailed description thereof that theforegoing description is intended to illustrate and not limit the scopeof the invention, which is defined by the scope of the following claims.Other aspects, advantages and modifications are within the scope of theclaims.

What is claimed:
 1. A composition comprising: leucine and at least oneof isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan,valine or histidine in free and/or salt form, wherein leucine, in freeand/or salt form, is present in an amount of at least 10% to about 35%by weight based on the weight of total amino acids.
 2. A compositioncomprising: leucine and at least one of isoleucine, lysine, methionine,phenylalanine, threonine, tryptophan, valine, or histidine in freeand/or salt form, wherein total leucine is present in an amount of atleast about 20% to about 35% by weight based on the weight of totalamino acids.
 3. A composition comprising: a) essential and, optionally,conditionally essential amino acids in free form and/or salt form, andb) intact protein, wherein total essential and, optionally,conditionally essential amino acids are present in an amount of about55% to about 75% by weight based on the weight of total amino acids. 4.The composition of claim 3, wherein the essential and, optionally,conditionally essential amino acids comprises leucine and at least oneof isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan,valine, or histidine.
 5. The composition of claim 4, wherein totalleucine is present in an amount of about 20% to about 35% by weightbased on the weight of total amino acids.
 6. The composition of claim 3further comprising arginine in free and/or salt form in an amount of atleast 5% to about 40% by weight based on the weight of total aminoacids.
 7. The composition of claim 3 further comprising methionine infree and/or salt form in an amount of at least about 0.5% to about 5% byweight based on the weight of total amino acids.
 8. The composition ofclaim 3, further comprising an n-3 polyunsaturated fatty acid.
 9. Thecomposition of claim 8, wherein the n-3 polyunsaturated fatty acid ischosen from α-linolenic acid, eicosapentaenoic acid and docosahexaenoicacid.
 10. The composition of claim 3, further comprising at least about1 g of eicosapentaenoic acid per serving or at least about 2 g ofeicosapentaenoic acid per daily dose.
 11. The composition of claim 3,further comprising tocopherol.
 12. The composition of claim 3, furthercomprising tocotrienol.
 13. The composition of claim 11, wherein thetocopherol is present in an amount about 50 mg per serving or at least150 mg per daily dose.
 14. The composition of claim 3, comprising fromabout 6 g to about 18 g amino acids in free and/or salt form per dailydose.
 15. The composition of claim 3, comprising from about 5 g to about10 g leucine in free and/or salt form per daily dose.
 16. Thecomposition of claim 3, comprising from about 6 g to about 21 g totalessential and/or conditionally essential amino acids per serving.
 17. Akit comprising: a) a first composition comprising: 1) essential and,optionally, conditionally essential amino acids in free form and/or saltform, and 2) intact protein, wherein total essential and, optionally,conditionally essential amino acids are present in an amount of about55% to about 75% by weight based on the weight of total amino acids; andb) a second composition comprising an anti-cancer drug.
 18. A method ofameliorating a condition associated with cachexia and/or anorexiacomprising the step of: administering to a human in need of suchamelioration a composition comprising a) essential and, optionally,conditionally essential amino acids in free form and/or salt form, andb) intact protein, wherein total essential and, optionally,conditionally essential amino acids are present in an amount of about55% to about 75% by weight based on the weight of total amino acids. 19.The method of claim 18, wherein the condition is chosen fromtumor-induced weight loss and muscle loss.
 20. The method of claim 18,wherein the administering is enterally administering.
 21. A method ofstimulating muscle protein synthesis comprising the step of:administering to a human in need of such stimulation a compositioncomprising a) essential and, optionally, conditionally essential aminoacids in free form and/or salt form, and b) intact protein, whereintotal essential and, optionally, conditionally essential amino acids arepresent in an amount of about 55% to about 75% by weight based on theweight of total amino acids.
 22. A method of reducing malnutritioncomprising the step of: administering to a human in need of suchreduction a composition comprising a) essential and, optionally,conditionally essential amino acids in free form and/or salt form, andb) intact protein, wherein total essential and, optionally,conditionally essential amino acids are present in an amount of about55% to about 75% by weight based on the weight of total amino acids.